NICOLA JUAN PABLO
Congresos y reuniones científicas
Título:
Functional Characterization of a Novel Iodide Transport Defect (ITD)-Causing Na+/I- Symporter (NIS) Mutation
Autor/es:
NICOLA, JP; SAENGER, P; MUZUMDAR, R; RODRIGUEZ-BURITICA, DF; GAMEZ GODOY, JD; CARRASCO, N
Lugar:
Vancouver
Reunión:
Congreso; Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting; 2014
Institución organizadora:
Pediatric Academic Societies and Asian Society for Pediatric Research
Resumen:
BACKGROUND: ITD is an uncommon cause of dyshormonogenetic congenital hypothyroidism that results from inactivating
mutations in the NIS gene. Clinical manifestations include low to absent thyroid and salivary iodide uptake and variable
degrees of hypothyroidism, goiter, and mental retardation.
OBJECTIVE: To characterize a novel NIS mutation on two sisters with primary hypothyroidism.
DESIGN/METHODS: Index patient presented at 7 3/12 years of age with severe primary hypothyroidism, growth failure and
delayed bone age. Thyroid autoantibodies were negative. US showed a multinodular gland. Thyroid uptake scan
demonstrated a decreased uptake of 5.4% and absent uptake in salivary glands. Her sibling, at 2.5 years, showed mild
hypothyroidism. Both had marked initial elevations of thyroglobulin that showed only mild decrease after treatment. The
genomic DNA encoding NIS was sequenced in the 2 sisters and parents, and in vitro functional studies of a newly identified
NIS mutation were carried out.
RESULTS: Both patients were compound heterozygous for mutations R124H/V270E. The R124H NIS mutant has previously
been identified as a cause of ITD. The newly identified V270E NIS mutation caused a substantial decrease in I- uptake when
expressed in COS-7 cells. Flow cytometry revealed a severe impairment in targeting of V270E NIS to the plasma membrane.
Strikingly, membrane vesicles from V270E NIS-expressing cells transport I- approximately as much as vesicles from
wild-type NIS-expressing cells, indicating that, although trafficking of V270E NIS to the cell surface is impaired, the protein
itself is highly functional. V270D also resulted in intracellular retention, indicating that a negative charge is not tolerated at
position 270. Remarkably, V270Q NIS is targeted to the cell surface.
CONCLUSIONS: We demonstrate that the V270E substitution reduces NIS targeting to the plasma membrane in two patients
with congenital hypothyroidism, thus causing a decrease in I- uptake even though V270E NIS is intrinsically active. This may
explain the unusual phenotype in the 7yr old index patient, who despite severe hypothyroidism is intellectually normal.
mutations in the NIS gene. Clinical manifestations include low to absent thyroid and salivary iodide uptake and variable
degrees of hypothyroidism, goiter, and mental retardation.
OBJECTIVE: To characterize a novel NIS mutation on two sisters with primary hypothyroidism.
DESIGN/METHODS: Index patient presented at 7 3/12 years of age with severe primary hypothyroidism, growth failure and
delayed bone age. Thyroid autoantibodies were negative. US showed a multinodular gland. Thyroid uptake scan
demonstrated a decreased uptake of 5.4% and absent uptake in salivary glands. Her sibling, at 2.5 years, showed mild
hypothyroidism. Both had marked initial elevations of thyroglobulin that showed only mild decrease after treatment. The
genomic DNA encoding NIS was sequenced in the 2 sisters and parents, and in vitro functional studies of a newly identified
NIS mutation were carried out.
RESULTS: Both patients were compound heterozygous for mutations R124H/V270E. The R124H NIS mutant has previously
been identified as a cause of ITD. The newly identified V270E NIS mutation caused a substantial decrease in I- uptake when
expressed in COS-7 cells. Flow cytometry revealed a severe impairment in targeting of V270E NIS to the plasma membrane.
Strikingly, membrane vesicles from V270E NIS-expressing cells transport I- approximately as much as vesicles from
wild-type NIS-expressing cells, indicating that, although trafficking of V270E NIS to the cell surface is impaired, the protein
itself is highly functional. V270D also resulted in intracellular retention, indicating that a negative charge is not tolerated at
position 270. Remarkably, V270Q NIS is targeted to the cell surface.
CONCLUSIONS: We demonstrate that the V270E substitution reduces NIS targeting to the plasma membrane in two patients
with congenital hypothyroidism, thus causing a decrease in I- uptake even though V270E NIS is intrinsically active. This may
explain the unusual phenotype in the 7yr old index patient, who despite severe hypothyroidism is intellectually normal.
